The invention relates to the derivatives, both known and novel, of maduranic acid and their use as inhibitors of proinflammatory cytokines for producing pharmaceuticals for the treatment of disorders mediated by these cytokines, and process for making.
The immune system is a complicated network of interactions of different types of cells and their mediators with one another. The mediators are intercellular signal molecules which regulate, for example, the growth, the differentiation and the function of the cells involved (K. F. Arai et al., Annu. Rev. Biochem. 59 (1990), 783). One important group of mediators are the cytokines, which include the colony-stimulating factors and the interleukins. Cytokines are polypeptides whose diverse molecular characteristics, mechanisms of action, physiological functions and the part played by them in numerous disorders are currently the subjects of intensive research.
Thus, it is known that a number of cytokines are responsible for the control of the immunological defensive responses to pathogens. B lymphocytes and T lymphocytes are of crucial importance for identifying exogenous particles or substances and for initiating the cascade of defensive responses (H. Holtmann, K. Resch, Naturwissensch. 82 (1995), 178). The proliferation, the functional differentiation and the cell activity, but also the rate of release of other cytokines, are controlled for these cells in particular by interleukin-2 (IL-2) and interleukin-4 (IL-4) (W. J. Pichler, Schweiz. Med. Wochenschr. 127 (1997), 341). Both cytokines also act on the enhanced provision of interleukin-5 (IL-5). Thus, IL-2 is able to stimulate the synthesis of IL-5 in T lymphocytes (G. P. Anderson, A. J. Coyle, TiPS 15 (1994), 324).
IL-4 controls T-cell differentiation to increase production of Th2 cells which preferentially produce IL-4 and IL-5 (A. Mori et al., Intern. Immun. 8 (1996), 1889). The action of these 3 cytokines eventually initiates the pathogen-controlling responses which can be manifested as inflammation.
Numerous diseases are thought to be connected with disturbances of this system. Thus, excessive responses to non-hazardous foreign materials can be the cause of allergically induced disorders such as, for example, asthma, rhinitis, conjunctivitis or dermatitis. Immunological protective responses after transplants can lead to unwanted rejection reactions.
Substances able to inhibit the action of interleukin-2,interleukin-4 and interleukin-5 should thus be of great therapeutic benefit for treating disorders mediated by these cytokines.
Glucocorticosteroids such as, for example, beclomethasone or budesonide which have potent antuinflammatory and immunosuppressant activity have been demonstrated to inhibit IL-2,IL-4 and IL-5 (P. J. Barnes, Eur. Respir. J. 9 (1996) Suppl. 22, 154 and J. Schmidt et al., Europ. J. Pharm. 260 (1994), 247). Side effects such as an increase in intraocular pressure, increased susceptibility to infection, impairment of the hormonal control system (osteoporosis, growth retardation in children) can limit the use of glucocorticosteroids. Finally, cyclosporin A (CsA) has also been found to have an inhibitory effect on the three cytokines (B. Ryffel, Pharmacol. Rev. 41 (1989), 407). In this case various side effects have also been found (for example nephrotoxicity) (D. Faulds, K. L. Goa, P. Benfield, Drugs 45 (1993), 953).
The aim of this invention is to provide very active inhibitors of the cytokines interleukin-2, interleukin-4 and interleukin-5 and to produce pharmaceuticals for the treatment of disorders mediated by these cytokines.
Maduranic acid or madurahydroxylactone is a natural product obtained from Actinomadura rubra by fermentation (DD 285 614: W. F. Fleck, D. G. Strauss, J. Meyer, Z. Allg. Mikrobiol. 18 (1978) 368-398). The structure of this compound (Formula 1) was elucidated by Paulus and co-workers (E. F. Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. C50 (1994) 2064-2067): 
Antibacterial effects, preferentially on Gram-positive bacteria, have been described for this compound and its alkyl homologues (W. F. Fleck et al., Z. Allg. Mikrobiol. 18 (1978), 389).
In addition, the synthesis of some maduraphthalazine derivatives of Formula 
for example with xe2x80x94R: xe2x80x94H, xe2x80x94CH3, xe2x80x94(CH2)2CH3, xe2x80x94(CH2)2OH, -phenyl and of Formula 3
for example with
R1xe2x95x90R2xe2x95x90R3xe2x95x90R4xe2x95x90xe2x80x94CH3,
R1xe2x95x90R2xe2x95x90R3xe2x95x90R4xe2x95x90xe2x80x94COCH3,
R1xe2x95x90R2xe2x95x90xe2x80x94H and R3xe2x95x90R4xe2x95x90xe2x80x94CH3,
R1xe2x95x90R2xe2x95x90xe2x80x94COCH3 and R3xe2x95x90R4xe2x95x90xe2x80x94CH3,
R1xe2x95x90R2xe2x95x90R4xe2x95x90xe2x80x94H, and R3xe2x95x90xe2x80x94COOCH3 
have been described, and their antimicrobial potential on some Gram-positive bacteria and bacterial gyrase have been investigated (E. Roemer et al., 4th Int. Conf. on Chemical Synthesis of Antibiotics and Related Microbial Products, Nashville, USA, 1994).
It has now been surprisingly found that both the previously known and many novel maduraphthalazines are able to inhibit the action of the cytokines interleukin-2, interleukin-4 and interleukin-5. Accordingly, these compounds are of great importance for producing pharmaceuticals for the therapy of disorders mediated by these cytokines. Thus, for example, it has been demonstrated that the compounds according to the present invention can inhibit the migration of eosinophilic granulocytes into the tissue which is characteristic of the asthmatic late phase reaction.
The invention thus relates to a process for inhibiting the action of the cytokines interleukin-2, interleukin4, and interleukin-5, which comprises administering to a patient in need therefore a compound of Formula 4
wherein
R1 is hydrogen, or branched-chain, or straight-chain C1-12alkyl residue optionally substituted one or m xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6-alkyl, xe2x80x94Sxe2x80x94C1-14aryl, xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94OSO2C1-6alkyl, xe2x80x94OSO2C6-14aryl, xe2x80x94(CS)R7, xe2x80x94O(CO)R7, xe2x80x94(CO)R9, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, wherein the C6-14aryl groups and the included carbocylic and heterocyclic substituents can be optionally substituted one or more times by R10,
a mono- or polyunsaturated, straight-chain or branched-chain C2-12alkenyl residue optionally substituted one or more times by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2,xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14-aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl, xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94OSO2C1-16alkyl, xe2x80x94OSO2C6-14aryl, xe2x80x94(CS)R7, xe2x80x94O(CO)R7, xe2x80x94(CO)R9, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, the C6-14 aryl groups and the included carbocyclic and heterocyclic substituents can be optionally substituted one or more times by R10,
mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, optionally substituted one or more times by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2,xe2x80x94NH C1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14aryl, xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94OSO2C1-6alkyl, xe2x80x94OSO2C6-14aryl, xe2x80x94(CS)R7, xe2x80x94O(CO)R7, xe2x80x94(CO)R9, the C6-14 aryl groups can be optionally substituted one or more times by R10,
a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, optionally substituted one or more times by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl, xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94OSO2C1-6alkyl, xe2x80x94OSOC2C6-14aryl, xe2x80x94(CS)R7, xe2x80x94O(CO)R7, xe2x80x94(CO)R8,
the C6-14aryl groups can be optionally substituted one or more times by R10, carbo- or a heterocyclic saturated or mono- or polyunsaturated spirocycles with 3-10 ring members, where heterocyclic systems contain 1-6 heteroatoms optionally substituted one or more times by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl, xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94OSO2C1-6 alkyl, xe2x80x94OSO2C6-14 aryl, xe2x80x94(CS)R7, xe2x80x94O(CO)R7, xe2x80x94(CO)R8,
the C6-14aryl groups can be optionally substituted one or more times by R10;
R2, R3, R4, R5, R6 can be the same or different and are hydrogen, and a straight-chain or branched-chain C1-6alkyl residue, optionally substituted one or more times by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2,xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CO)R8, xe2x80x94(CS)R7, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C1-14aryl, xe2x80x94SOR8, xe2x80x94SO2R8, COxe2x80x94C1-6alkyl,
optionally substituted one or more times by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CO)R8, xe2x80x94(CS)R7, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl, xe2x80x94SO8, xe2x80x94SO2R8 
COOxe2x80x94C1-6alkyl residue, optionally substituted one or more times by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CO)R8, xe2x80x94(CS)R7, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl, xe2x80x94SOR8, xe2x80x94SO2R8;
R7 is a C1-6alkyl, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94NH2, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl residue, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms,
R8 is xe2x80x94H, a xe2x80x94C1-6alkyl, xe2x80x94NH2,xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl, xe2x80x94NHCOR7, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl), xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl residue, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms;
R9 is xe2x80x94H, a xe2x80x94C1-6alkyl residue, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, or a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms,
R10 is xe2x80x94OH, a xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94NHC6-14aryl, xe2x80x94N(C6-14aryl)2, xe2x80x94N(C1-6alkyl)(C6-14aryl), xe2x80x94NHCOR7, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CO)R8, xe2x80x94(CS)R7, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C6-14aryl, xe2x80x94O(CO)R7, xe2x80x94Sxe2x80x94C1-6alkyl, xe2x80x94Sxe2x80x94C6-14aryl, xe2x80x94SOR8, or an xe2x80x94SO2R8 residue and
A, B can be a xe2x80x94CH2xe2x80x94, xe2x80x94CH(OH) residue or
A+B can be a xe2x80x94CHxe2x95x90CHxe2x80x94 residue, or
with a pharmaceutically acceptable salt thereof
The invention also relates to compounds and salts of Formula 4, wherein R1 through R9 have the same meanings as above, provided that R2 through R5 are not hydrogen when R6 is CH3.
The pharmacologically acceptable salts are obtained in a conventional manner by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. Examples of suitable inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, and of organic acids are carboxylic or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfomic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid. Examples of suitable inorganic bases are sodium hydroxide solution, potassium hydroxide solution, ammonia, and of organic bases are amines, suitably tertiary amines such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, -picoline, -picoline, -picoline, quinaldine or pyrimidine.
It is furthermore possible to obtain pharmacologically suitable salts of the compounds of Example 4 by converting derivatives which have tertiary amino groups into the corresponding quaternary ammonium salts with quaternizing agents in a manner known per se. Examples of suitable quaternizing agents are alkyl halides such as methyl iodide, ethyl bromide and n-propyl chloride, but also arylalkyl halides such as benzyl chloride or 2-phenylethyl bromide.
The invention further relates to the D form, the L form and D,L mixtures of compounds of Formula 4 which contain an asymmetric carbon atom and, in the case of a plurality of asymmetric carbon atoms, the diastereomeric forms. Compounds of Formula 4 which contain asymmetric carbon atoms and are usually obtained as racemates can be separated into the optically active isomers in a manner known per se, for example using an optically active acid. However, it is also possible to employ from the outset an optically active starting substance, in which case the final product obtained is a corresponding optically active or diastereomeric compound. p The invention relates to the use of the compounds of the present invention or their pharmacologically acceptable salts as inhibitors of the cytokines IL-2,IL-4 and IL-5 for producing pharmaceuticals for the treatment of disorders mediated by these cytokines.
These disorders include, for example, bronchial asthma, allergic rhinitis, allergic conjunctivitis, a topic dermatitis, eczemas, allergic angiitis, inflammations mediated by eosinophils, such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome, autoimmune diseases such as rheumatoid arthritis, rheumatoid spondylitis, lupus erythematosus, multiple sclerosis, psoriasis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus and sepsis.
The compounds according to the invention or their pharmacologically acceptable salts are also useful to produce pharmaceuticals for preventing rejection reactions after transplants of cells, tissues or organs. These pharmaceuticals are produced using an effective dose of the compounds according to the invention or their salts, in addition to conventional excipients, carriers and additives.
The dosage of the active ingredients can vary depending on the route of administration, age, weight of the patient, nature and severity of the disorders to be treated and similar factors. The daily dose can be given as a single dose to be administered once or divided into two or more doses a day, and is, generally between, 0.001 and 100 mg.
Oral, parenteral, intravenous, transdermal, topical, inhalation and intranasal preparations are suitable as administration forms.
Conventional pharmaceutical formulations are suitably used, such as tablets, coated tablets, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrups or drops.
Solid drug forms may contain inert ingredients and carriers such as, for example, calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminium stearate, methylcellulose, talc, highly disperse silicas, silicone oil, higher molecular weight fatty acids (such as stearic acid), agar-agar or vegetable or animal fats and oils, solid high molecular weight polymers (such as polyethylene glycol); preparations suitable for oral administration may, if desired, contain additional flavorings and/or sweeteners.
Liquid drug forms may be sterilized and/or where appropriate contain excipients such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols to control the osmotic pressure or for buffering and/or viscosity regulators. Examples of additions of these types are tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). Suitable for controlling the viscosity are high molecular weight polymers such as, for example, liquid polyethylene oxide, microcrystalline celluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatin. Examples of solid carriers are starch, lactose, mannitol, methylcellulose, talc, highly disperse silicas, higher molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers such as polyethylene glycol.
Oily suspensions for parenteral or topical uses may contain vegetable, synthetic or semisynthetic oils such as, for example, liquid C8-22 fatty acid esters, for example palmitic, lauric, tridecylic, margaric, stearic, arachic, myristic, behenic, pentadecylic, linoleic, elaidic, brassidic, erucic or oleic acid, which are esterified with C1-6 mono- to trihydric alcohols such as methanol, ethanol, propanol, butanol, pentanol or isomers thereof, glycol or glycerol. Examples of fatty acid esters of these types are commercially available Miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters such as artificial duck preen gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters inter alia. Likewise suitable are silicone oils varying in viscosity or fatty alcohols such as isotridecyl alcohol, 2-octyl dodecanol, cetyl stearyl alcohol or oleyl alcohol, fatty acids such as, for example, oleic acid. It is furthermore possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soya oil.
Suitable solvents, gel forners and solubilizers are water or water-miscible solvents. Suitable examples are ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, also phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, Methylcellosolve, Cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
Film formers which can be used are cellulose ethers which may dissolve or partly swell both in water and in organic solvents, such as, for example, hydroxypropylmethylcellulose, methylcellulose, ethyl-cellulose or soluble starches.
Mixed forms between gel formers and film formers are likewise possible. Used in this case are, in particular, ionic macromolecules such as, for example, sodium carboxymethylcelluose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
Further formulation aids which can be employed include glycerol, paraffin of varying viscosity, triethanolarmine, collagen, allantoin, novantisolic acid. It may also be necessary to use surfactants, emulsifiers or wetting agents for formulation, such as, for example, Na lauryl sulfate, fatty alcohol ether sulfates, di-Na N-lauryl-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (for example as sold under the name Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono/dialkyl polyglycol ether orthophosphoric acid monoethanolamine salts.
Stabilizers such as montmorillonite or colloidal silicas for stabilizing emulsions or for preventing the breakdown of the active substances such as antioxidants, for example tocopherols or butylated hydroxyanisole, or preservatives such as p-hydroxybenzoic esters, can likewise be used where appropriate for preparing the required formulations.
The products are manufactured and filled into containers and sealed under the usual antimicrobial and aseptic conditions.